Causal statistical association between remnant cholesterol and coronary heart disease: genetic insights into the PSRC1–CELSR2–SORT1 gene cluster

Remnant cholesterol (RC) is increasingly recognized as an independent contributor to coronary heart disease (CHD) risk beyond LDL-C. However, its causal roles, genetic determinants, tissue-specific regulation, and relevance across ancestrally diverse populations remain incompletely characterized. Associations between RC and incident CHD were evaluated in the UK Biobank (UKB) employing Cox regression and restricted cubic splines models, including subgroup analyses by LDL-C levels. Causality was assessed using two-sample Mendelian randomization (MR) and colocalization using genome-wide summary statistics from UKB and FinnGen. Findings were validated in a multiancestry dataset. Genetic regulatory mechanisms were explored using tissue-specific MR integrating expression quantitative trait locus. Lipid-wide MR was used to evaluate gene effects across multiple lipid traits. Comparison between identified genes and established lipid-modifying target genes was conducted. RC showed a size-specific, LDL-C-independent association with CHD, which remained strong among individuals with normal LDL-C (<2.6 mmol/l). Multivariable MR confirmed a robust causal relationship. Colocalization identified shared signals at the PSRC1-CELSR2-SORT1 locus, with lead variants rs12740347 and rs646776. This cluster exhibited liver-specific inverse associations with CHD, pleiotropic effects on lipid traits, and stronger influence on RC than well-known targets such as HMGCR and PCSK9. RC represents a potentially modifiable marker of CHD risk, especially in individuals with normal LDL-C. Hepatic expression of PSRC1-CELSR2-SORT1 protects against CHD via RC reduction, independent of LDL-C, supporting RC as promising target for CHD prevention.